Project Summary/Abstract Many signaling pathways linked to aging are linked to the regulation of metabolic signaling and stress response pathways. For instance, the target of rapamycin (TOR) pathway is an evolutionarily-conserved nutrient-sensing protein kinase that regulates growth and metabolism in all eukaryotic cells. Two complexes, mTORC1 and 2, have overlapping upstream regulators and downstream effectors. Reduced mTOR signaling, either by genetic intervention or with the clinically approved drug rapamycin, extends longevity in mice (as well as yeast, worms and flies) and delays many pathologies of aging. Given its central role in aging and metabolism, it is critical to understand how different perturbations of the mTOR pathway impact aging and metabolism. Here, we use mouse models and cell culture studies to test one of the major downstream targets of mTORC1, 4E-BP1. Justifying the emphasis on 4E-BP1, enhanced 4E-BP activity is associated with lifespan extension in worms and flies, and we find that transgenic mice overexpressing 4E-BP1 are resistant to high fat diet-induced metabolic dysfunction. We will employ multiple mouse models of 4E-BP1 overexpression in both overnutrition and aging studies. Preliminary data indicates that an inflammation-induced loss of 4E-BP1 expression in the context of a high fat diet underlies the specific propensity of males to become glucose intolerant and insulin resistant. We will determine the mechanisms underlying this gender dimorphism and its impact on the mTOR pathway. Gender-specific responses to diet and aging are rampant in mouse models and in humans, but the underlying causes of gender-specificity is largely unknown. In addition, we will determine why muscle specific activation of 4E-BP1 preserves both skeletal muscle function and brown fat content during overnutrition and aging, focusing on recent findings linking the benefits to skeletal muscle production and secretion of the myokine, FGF21. Together, these studies will yield several new insights regarding the specifics of mTOR signaling in the context of aging and metabolism, providing a better understanding about how this pathway modulates aging and linking modulation of the mTOR pathway to other pharmacologic interventions in aging.